EP1198249B1 - Utilisation de cpg comme adjuvant de vaccin contre le vih - Google Patents

Utilisation de cpg comme adjuvant de vaccin contre le vih Download PDF

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EP1198249B1
EP1198249B1 EP00943919A EP00943919A EP1198249B1 EP 1198249 B1 EP1198249 B1 EP 1198249B1 EP 00943919 A EP00943919 A EP 00943919A EP 00943919 A EP00943919 A EP 00943919A EP 1198249 B1 EP1198249 B1 EP 1198249B1
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cpg
vaccine
hiv
nef
oligonucleotide
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EP1198249A2 (fr
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Nathalie Garcon
Gerald Voss
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GlaxoSmithKline Biologicals SA
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GlaxoSmithKline Biologicals SA
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Priority claimed from GB0002200A external-priority patent/GB0002200D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to new vaccine formulations and their use in the treatment or prophylaxis of HIV infections.
  • the invention relates to the use of HIV antigen in conjunction with a CpG oligonucleotide.
  • HIV is the primary cause of AIDS (acquired immune deficiency syndrome) and is regarded, as one of the worlds most pressing health issues. Although there has been extensive efforts to produce a successful vaccine, efforts to-date have failed to produce one. Accordingly, there remains a need for an improved HIV immunogenic composition.
  • Immunomodulatory oligonucleotides contain unmethylated CpG dinucleotides ("CpG”) and are known (WO 96/02555, EP 468520).
  • CpG is an abbreviation for cytosine-guanosine dinucleotide motifs present in DNA. Historically, it was observed that the DNA fraction of BCG could exert an anti-tumour effect.
  • synthetic oligonucleotides derived from BCG gene sequences were shown to be capable of inducing immunostimulatory effects (both in vitro and in vivo). The authors of these studies concluded that certain palindromic sequences, including a central CG motif, carried this activity.
  • CG motif has to be in a certain sequence context, and that such sequences are common in bacterial DNA but are rare in vertebrate DNA.
  • Purine Purine CG pyrimidine pyrimidine and where the CG motif is not methylated In certain combinations of the six nucleotides a palindromic sequence is present. Several of these motifs, either as repeats of one motif or a combination of different motifs, can be present in the same oligonucleotide. The presence of one or more of these immunostimulatory sequence containing oligonucleotides can activate various immune subsets, including natural killer cells (which produce interferon ⁇ and have cytolytic activity) and macrophages (Wooldrige et al Vol 89 (no. 8), 1977). Although other unmethylated CpG containing sequences not having this consensus sequence have now been shown to be immunomodulatory.
  • the present invention provides an improved vaccine formulation comprising a CpG oligonucleotide and an HIV antigen selected from the group HIV gp160, HIV gp120; an HIV Nef protein or derivative thereof linked to either (i) a fusion partner or (ii) an HIV Tat protein or derivative thereof; or an HIV Tat protein or derivative thereof linked to either (i) a fusion protein or (ii) an HIV Nef protein or derivative thereof; or an HIV Nef protein or derivative thereof linked to an HIV Tat protein or derivative thereof and a fusion partner.
  • 'fusion partner' is meant any protein sequence that is not Tat or Nef.
  • the fusion partner is protein D or its lipidated derivative Lipoprotein D, from Haemophilius influenzae B.
  • the N-terminal third i.e. approximately the first 100-130 amino acids are utilised. This is represented herein as Lipo D 1/3.
  • the Nef protein or derivative thereof may be linked to the Tat protein or derivative thereof.
  • Such Nef-Tat fusions may optionally also be linked to a fusion partner, such as protein D.
  • the fusion partner is normally linked to the N-terminus of the Nef or Tat protein.
  • Derivatives encompassed within the present invention include molecules with a C terminal Histidine tail, which preferably comprises between 5-10 Histidine residues. Generally, a histidine tail containing n residues is represented herein as His (n). The presence of a histidine (or 'His') tail aids purification. More specifically, the invention provides vaccines comprising proteins with the following structure: Lipo D 1/3 Nef His ( 6 ) Lipo D 1/3 Nef-Tat His ( 6 ) Prot D 1/3 Nef His ( 6 ) Prot D 1/3 Nef-Tat His ( 6 ) Nef-Tat His ( 6 )
  • the proteins are expressed with a Histidine tail comprising between 5 to 10 and preferably six Histidine residues. These are advantageous in aiding purification.
  • yeast Sacharomyces cerevisiae
  • Nef Macreadie IG et al 1993, Yeast 9 (6) 565-573
  • Tat Braindock M et al, 1989, Cell 58 (2) 269-79
  • the present invention also provides vaccines comprising Nef and/or Tat separately.
  • the DNA and amino acid sequences of representative Nef-His, Tat-His and of Nef-Tat-His fusion proteins as set forth in WO99/16884.
  • Particularly preferred vaccines according to the invention comprise an HIV fusion protein such as Nef-Tat and optionally an additional HIV protein.
  • Particularly preferred in a vaccine formulation according to the invention is a combination of an HIV fusion protein plus gp120, more particularly Nef-Tat with gp120.
  • Derivatives encompassed within the present invention also include mutated proteins.
  • the term 'mutated' is used herein to mean a molecule which has undergone deletion, addition or substitution of one or more amino acids using well known techniques for site directed mutagensis or any other conventional method.
  • Vaccine preparation is generally described in Vaccine Design - The subunit and adjuvant approach (Ed. Powell and Newman) Pharmaceutical Biotechnology Vol. 6 Plenum Press 1995. Encapsulation within liposomes is described by Fullerton, US Patent 4,235,877.
  • the preferred oligonucleotides preferably contain two or more CpG motifs separated by six or more nucleotides.
  • the oligonucleotides of the present invention are typically deoxynucleotides.
  • the internucleotide in the oligonucleotide is phosphorodithioate, or more preferably a phosphorodithioate bond, although phosphodiester and other internucleotide bonds are within the scope of the invention including oligonucleotides with mixed interaucleotide linkages.
  • Preferred oligonucleotides have the following sequences:
  • a + in the Thio column indicates the presence of a thioate modification.
  • 'Mix' indicates a mixture of thioate modification and sequence without thioate modification (the asterisks indicate the linkages with a thioate modification).
  • a - in the Thio column indicates absence of a thioate modification.
  • a + in the CpG column indicates a the presence of a CpG motif and a - in the CpG column indicates absence of a CpG motif.
  • WD1005 contains a GpC rather than a CpG motif, thus it is marked with a - in the CpG column of the table.
  • WD1007 contains a palindromic motif (GACGTC) as well as other non-palindromic CpG sequences. This is also within the scope of a CpG oligonucleotide as the term is used in the present application.
  • the CpG oligonucleotides utilised in the present invention may be synthesized by any method known in the art (eg EP 0 468 520). Conveniently, such oligonucleotides may be synthesized utilising an automated synthesizer. Methods for producing phosphorothioate oligonucleotides or phosphorodithioate are described in US 5,666,153, US 5,278,302 and WO 95/26204.
  • each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 ⁇ g of protein, preferably 2-500 ⁇ g, most preferably 5-250 ⁇ g. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisations adequately spaced.
  • a method of treating a human in need thereof either with a vaccine composition comprising an HIV antigen and a CpG oligonucleotide (as hereinabove defined) or with the CpG oligonucleotide followed after a suitable time by the HIV antigen.
  • kits comprising effective amounts of a CpG oligonucleotide-containing formulation for use as a priming formulation for pre-administration to human patients and an HIV antigen for injection at some suitable time later, as described hereinabove.
  • Preferred CpG oligonucleotides are those indicated in the table hereinabove.
  • the CpG will be present in the range 10 ⁇ g per dose to 2000 ⁇ g, preferably 50-1000 ⁇ g, such as about 50 or about 500 or about 1000 ⁇ g per dose.
  • the vaccine used in the present invention may comprise a carrier such as an aluminium salt, eg aluminium hydroxide (Al(OH) 3 ), aluminium phosphate or aluminium phosphate sulfate (alum), or a non-toxic oil in water emulsion or a mixture thereof.
  • a carrier such as an aluminium salt, eg aluminium hydroxide (Al(OH) 3 ), aluminium phosphate or aluminium phosphate sulfate (alum), or a non-toxic oil in water emulsion or a mixture thereof.
  • an aluminium salt preferably aluminium hydroxide
  • it is generally present in the range of 50 to 100 ⁇ g, preferably 100 to 500 ⁇ g per dose.
  • Non-toxic oil in water emulsions preferably contain a non-toxic oil, eg squalene and an emulsifier such as (polysorbitan monoleate) Tween 80, in an aqueous carrier such as phosphate buffered saline.
  • a non-toxic oil eg squalene and an emulsifier such as (polysorbitan monoleate) Tween 80
  • an aqueous carrier such as phosphate buffered saline.
  • the vaccine used in the present invention may comprise an additional adjuvant, preferably a saponin adjuvant such as QS21 as described for example in WO 9517210, optionally in the presence of a sterol, such as cholesterol as described for example in PCT/EP96/01464.
  • the vaccine of the invention may also comprise monophosphoryl lipid A and derivatives thereof known in the art.
  • a preferred derivative is 3 de-O-acylated monophosphoryl lipid A, described in British Patent No. GB 2 220 211.
  • vaccine formulations of the present invention may additionally comprise other pharmaceutical excipients or immunostimulants.
  • the vaccine formulation additionally comprises an aluminium salt, preferably aluminium hydroxide.
  • a saponin adjuvant may also be included such as QS21 (Aquila).
  • Formulations were prepared one day before each injection. All incubations were carried out at room temperature with agitation.
  • Gp120 (50 ⁇ g) was adsorbed on 500 ⁇ g of Al(OH) 3 for 1 hour.
  • the formulation was buffered with a 10-fold concentrated PO 4 /NaCl pH 6.8 solution before addition of 500 ⁇ g of WD001. After 15 min, 50 ⁇ g/ml of thiomersal was added as preservative.
  • Gp120 (50 ⁇ g) was diluted in PO 4 /NaCl buffer pH 6.8 before addition of 500 ⁇ g of CpG WD001. After 15 min, 50 ⁇ g/ml of thiomersal was added as preservative.
  • rhesus monkeys Five rhesus monkeys (Macaca mulatta ). per group were immunized twice intramuscularly with 500 ⁇ l of vaccine at a four-week-interval. Sera and peripheral blood mononuclear cells (PBMC) were taken at several occasions.
  • PBMC peripheral blood mononuclear cells
  • Gp 120-specific antibodies in sera of immunized monkeys were determined in an ELISA as described in Mooij et al., 1998. Briefly, ELISA plates were coated with 1 ⁇ g/ml gp120, saturated with BSA and subjected to incubation with rhesus monkey sera followed by ⁇ -human biotinylated antibody. Finally, HRP-streptavidin was added and quantified in a color reaction using OPD as substrate.
  • IFN- ⁇ -secreting cells were investigated in all monkeys before immunization and 6 days after the second dose. IFN- ⁇ -secreting cells could not be evaluated from pre-immunization samples due to technical difficulties. However, such cells were detectable after secondary immunization (Figure 3). All animals in both groups exhibited an antigen-specific response.
  • Immunization with HIV-1 gp120 in combination with CpG or CpG/alum induces immune responses in non-human primates. These responses include gp120-specific antibodies, lymphoproliferation and IFN- ⁇ -secreting cells.
  • the antigens prepared according to WO99/16884 were dialysed against NaCl 150mM to eliminate the PO 4 ions that inhibit the adsorption of gp 120 on Al(OH) 3 .
  • the antigens were incubated with the CpG before adsorption on Al(OH) 3 to favour a potential interaction between the His tail of the Nef-Tat and Nef antigens and the oligonucleotide.
  • the formulation was centrifuged and the supernatant was analsyed by SDS-PAGE (Novex 4-20 % , reducing conditions) to check the adsorption of HIV Nef-Tat.
  • the gel was stained with silver. Gel analysis of the formulation revealed that most of the Nef or Nef-Tat protein was adsorbed onto alum.
  • a vaccine formulation was prepared in accordance with the invention comprising a Nef-Tat fusion protein and gp120 together with an oligonucleotide containing unmethylated CpG dinucleotide motifs and aluminium hydroxide as carrier.
  • CpG dry powder is dissolved in H 2 O to give a solution of 5 mg/ml CpG.
  • the 3 antigens were dialyzed against NaCl 150 mM to eliminate the phosphate ions that inhibit the adsorption of gp120 on aluminium hydroxide.
  • the antigens diluted in H 2 O (100 ⁇ g gp120, 20 ⁇ g NefTat and 20 ⁇ g SIV Nef) were incubated with the CpG solution (500 ⁇ g CpG) for 30 min before adsorption on Al(OH) 3 to favor a potential interaction between the His tail of NefTat and Nef antigens and the oligonucleotide (stronger immunostimulatory effect of CpG described when bound to the antigen compared to free CpG). Then Al(OH) 3 (500 ⁇ g), 10 fold concentrated NaCl and 1 ⁇ g/ml thiomersal as preservative were consecutively added at 5 min intervals.
  • CD4-positive cells declined after challenge. All four animals exhibited a slight decrease in CD4-positive cells and recovered to baseline levels over time (Figure 4). In contrast, three out of four animals in an adjuvant alone control group exhibited a drop of CD4-positive cells below 5 % and never recovered.
  • Virus load data are almost the inverse of CD4 data ( Figure 5). Virus load decreased in the animals that had received NefTat + gp120 formulated with CpG containing oligonucleotide, but remained high in three out of four control animals which received only an adjuvant.
  • HIV-1 subunit vaccine protects rhesus macaques from in vivo passaged simian-human immunodeficiency virus infection. AIDS 12 :F15-F22.

Claims (12)

  1. Formulation de vaccin comprenant une association d'une protéine de fusion du VIH plus gp120 et d'un oligonucléotide CpG immunostimulateur.
  2. Vaccin selon la revendication 1 dans lequel la protéine de fusion du VIH est une protéine de fusion Nef-Tat.
  3. Vaccin selon la revendication 1 ou 2 dans lequel la protéine Nef-Tat est fusionnée à la protéine D, ou à la lipoprotéine D ou à un de ses fragments, d'Haemophilius influenzae.
  4. Formulation de vaccin selon l'une quelconque des revendications 1 à 3 comprenant en outre un sel d'aluminium ou un adjuvant saponine.
  5. Vaccin selon l'une quelconque des revendications 1 à 4 dans lequel l'oligonucléotide comprend deux dinucléotides CpG.
  6. Vaccin selon l'une quelconque des revendications 1 à 5 dans lequel l'oligonucléotide CpG a une longueur d'entre 15 et 45 nucléotides.
  7. Vaccin selon l'une quelconque des revendications 1 à 6 dans lequel l'oligonucléotide est choisi dans le groupe :
    Figure 00210001
  8. Vaccin selon l'une quelconque des revendications 1 à 7 dans lequel l'oligonucléotide CpG comprend au moins une liaison inter-nucléotidique phosphorothioate.
  9. Utilisation d'une protéine de fusion du VIH plus gp120 et d'un oligonucléotide CpG immunostimulateur pour fabriquer un médicament pour la prévention ou l'amélioration d'une infection par le VIH chez un patient.
  10. Vaccin selon l'une quelconque des revendications 1 à 9 destiné à être utilisé comme un médicament.
  11. Procédé pour produire un vaccin selon l'une quelconque des revendications 1 à 8 comprenant le mélange d'une protéine de fusion du VIH plus gp120 et d'un oligonucléotide immunostimulateur CpG.
  12. Kit comprenant des quantités efficaces d'une formulation contenant l'oligonucléotide CpG destiné à être utilisé comme formulation d'amorçage pour une pré-administration à des patients humains et une protéine de fusion du VIH plus gp120 pour injection à un moment ultérieur adapté.
EP00943919A 1999-06-29 2000-06-28 Utilisation de cpg comme adjuvant de vaccin contre le vih Expired - Lifetime EP1198249B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB9915205.0A GB9915205D0 (en) 1999-06-29 1999-06-29 Vaccine
GB9915205 1999-06-29
GB0002200A GB0002200D0 (en) 2000-01-31 2000-01-31 Novel use
GB0002200 2000-01-31
PCT/EP2000/005998 WO2001000232A2 (fr) 1999-06-29 2000-06-28 Vaccin

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EP1198249A2 EP1198249A2 (fr) 2002-04-24
EP1198249B1 true EP1198249B1 (fr) 2005-10-19

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US (1) US20080199494A1 (fr)
EP (1) EP1198249B1 (fr)
AT (1) ATE306938T1 (fr)
AU (1) AU5821000A (fr)
CA (1) CA2376992A1 (fr)
DE (1) DE60023300T2 (fr)
ES (1) ES2250151T3 (fr)
WO (1) WO2001000232A2 (fr)

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US7935351B2 (en) 2001-12-20 2011-05-03 The United States Of America As Represented By The Department Of Health And Human Services Use of CPG oligodeoxynucleotides to induce angiogenesis
US7959934B2 (en) 2001-08-14 2011-06-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method for rapid generation of mature dendritic cells
US7960356B2 (en) 1999-04-12 2011-06-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Oligodeoxynucleotide and its use to induce an immune response
US8263091B2 (en) 2002-09-18 2012-09-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method of treating and preventing infections in immunocompromised subjects with immunostimulatory CpG oligonucleotides
US8466116B2 (en) 2001-12-20 2013-06-18 The Unites States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of CpG oligodeoxynucleotides to induce epithelial cell growth

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US7960356B2 (en) 1999-04-12 2011-06-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Oligodeoxynucleotide and its use to induce an immune response
US8227446B2 (en) 1999-04-12 2012-07-24 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Oligodeoxynucleotide and its use to induce an immune response
US7666674B2 (en) 2001-07-27 2010-02-23 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of sterically stabilized cationic liposomes to efficiently deliver CPG oligonucleotides in vivo
US7959934B2 (en) 2001-08-14 2011-06-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method for rapid generation of mature dendritic cells
US7935351B2 (en) 2001-12-20 2011-05-03 The United States Of America As Represented By The Department Of Health And Human Services Use of CPG oligodeoxynucleotides to induce angiogenesis
US8466116B2 (en) 2001-12-20 2013-06-18 The Unites States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of CpG oligodeoxynucleotides to induce epithelial cell growth
US8263091B2 (en) 2002-09-18 2012-09-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method of treating and preventing infections in immunocompromised subjects with immunostimulatory CpG oligonucleotides

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WO2001000232A2 (fr) 2001-01-04
CA2376992A1 (fr) 2001-01-04
ATE306938T1 (de) 2005-11-15
EP1198249A2 (fr) 2002-04-24
ES2250151T3 (es) 2006-04-16
DE60023300T2 (de) 2006-07-06
WO2001000232A3 (fr) 2001-05-25
AU5821000A (en) 2001-01-31
DE60023300D1 (de) 2006-03-02
US20080199494A1 (en) 2008-08-21

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